Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides
Neoantigen formation due to the interaction of drug molecules with human leukocyte antigen (HLA)-peptide complexes can lead to severe hypersensitivity reactions. Flucloxacillin (FLX), a β-lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.629399/full |
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doaj-57a65f7c16ba491cbcf73a5ec2561268 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Montserrat Puig Suryatheja Ananthula Ramesh Venna Swamy Kumar Polumuri Elliot Mattson Lacey M. Walker Marco Cardone Mayumi Takahashi Shan Su Lisa F. Boyd Kannan Natarajan Galina Abdoulaeva Wells W. Wu Gregory Roderiquez William H. Hildebrand Serge L. Beaucage Zhihua Li David H. Margulies Michael A. Norcross |
| spellingShingle |
Montserrat Puig Suryatheja Ananthula Ramesh Venna Swamy Kumar Polumuri Elliot Mattson Lacey M. Walker Marco Cardone Mayumi Takahashi Shan Su Lisa F. Boyd Kannan Natarajan Galina Abdoulaeva Wells W. Wu Gregory Roderiquez William H. Hildebrand Serge L. Beaucage Zhihua Li David H. Margulies Michael A. Norcross Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides Frontiers in Immunology flucloxacillin HLA-B*57:01 drug hypersensitivity hapten immunogenicity transgenic mice |
| author_facet |
Montserrat Puig Suryatheja Ananthula Ramesh Venna Swamy Kumar Polumuri Elliot Mattson Lacey M. Walker Marco Cardone Mayumi Takahashi Shan Su Lisa F. Boyd Kannan Natarajan Galina Abdoulaeva Wells W. Wu Gregory Roderiquez William H. Hildebrand Serge L. Beaucage Zhihua Li David H. Margulies Michael A. Norcross |
| author_sort |
Montserrat Puig |
| title |
Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides |
| title_short |
Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides |
| title_full |
Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides |
| title_fullStr |
Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides |
| title_full_unstemmed |
Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides |
| title_sort |
alterations in the hla-b*57:01 immunopeptidome by flucloxacillin and immunogenicity of drug-haptenated peptides |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2021-02-01 |
| description |
Neoantigen formation due to the interaction of drug molecules with human leukocyte antigen (HLA)-peptide complexes can lead to severe hypersensitivity reactions. Flucloxacillin (FLX), a β-lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune-mediated drug-induced liver injury caused by an influx of T-lymphocytes targeting liver cells potentially recognizing drug-haptenated peptides in the context of HLA-B*57:01. To identify immunopeptidome changes that could lead to drug-driven immunogenicity, we used mass spectrometry to characterize the proteome and immunopeptidome of B-lymphoblastoid cells solely expressing HLA-B*57:01 as MHC-I molecules. Selected drug-conjugated peptides identified in these cells were synthesized and tested for their immunogenicity in HLA-B*57:01-transgenic mice. T cell responses were evaluated in vitro by immune assays. The immunopeptidome of FLX-treated cells was more diverse than that of untreated cells, enriched with peptides containing carboxy-terminal tryptophan and FLX-haptenated lysine residues on peptides. Selected FLX-modified peptides with drug on P4 and P6 induced drug-specific CD8+ T cells in vivo. FLX was also found directly linked to the HLA K146 that could interfere with KIR-3DL or peptide interactions. These studies identify a novel effect of antibiotics to alter anchor residue frequencies in HLA-presented peptides which may impact drug-induced inflammation. Covalent FLX-modified lysines on peptides mapped drug-specific immunogenicity primarily at P4 and P6 suggesting these peptide sites as drivers of off-target adverse reactions mediated by FLX. FLX modifications on HLA-B*57:01-exposed lysines may also impact interactions with KIR or TCR and subsequent NK and T cell function. |
| topic |
flucloxacillin HLA-B*57:01 drug hypersensitivity hapten immunogenicity transgenic mice |
| url |
https://www.frontiersin.org/articles/10.3389/fimmu.2020.629399/full |
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doaj-57a65f7c16ba491cbcf73a5ec25612682021-02-09T05:00:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011110.3389/fimmu.2020.629399629399Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated PeptidesMontserrat Puig0Suryatheja Ananthula1Ramesh Venna2Swamy Kumar Polumuri3Elliot Mattson4Lacey M. Walker5Marco Cardone6Mayumi Takahashi7Shan Su8Lisa F. Boyd9Kannan Natarajan10Galina Abdoulaeva11Wells W. Wu12Gregory Roderiquez13William H. Hildebrand14Serge L. Beaucage15Zhihua Li16David H. Margulies17Michael A. Norcross18Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Translational Science, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Biological Chemistry, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesMolecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesMolecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesFacility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesFacility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesDepartment of Microbiology and Immunology, School of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesLaboratory of Biological Chemistry, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Translational Science, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesMolecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United StatesNeoantigen formation due to the interaction of drug molecules with human leukocyte antigen (HLA)-peptide complexes can lead to severe hypersensitivity reactions. Flucloxacillin (FLX), a β-lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune-mediated drug-induced liver injury caused by an influx of T-lymphocytes targeting liver cells potentially recognizing drug-haptenated peptides in the context of HLA-B*57:01. To identify immunopeptidome changes that could lead to drug-driven immunogenicity, we used mass spectrometry to characterize the proteome and immunopeptidome of B-lymphoblastoid cells solely expressing HLA-B*57:01 as MHC-I molecules. Selected drug-conjugated peptides identified in these cells were synthesized and tested for their immunogenicity in HLA-B*57:01-transgenic mice. T cell responses were evaluated in vitro by immune assays. The immunopeptidome of FLX-treated cells was more diverse than that of untreated cells, enriched with peptides containing carboxy-terminal tryptophan and FLX-haptenated lysine residues on peptides. Selected FLX-modified peptides with drug on P4 and P6 induced drug-specific CD8+ T cells in vivo. FLX was also found directly linked to the HLA K146 that could interfere with KIR-3DL or peptide interactions. These studies identify a novel effect of antibiotics to alter anchor residue frequencies in HLA-presented peptides which may impact drug-induced inflammation. Covalent FLX-modified lysines on peptides mapped drug-specific immunogenicity primarily at P4 and P6 suggesting these peptide sites as drivers of off-target adverse reactions mediated by FLX. FLX modifications on HLA-B*57:01-exposed lysines may also impact interactions with KIR or TCR and subsequent NK and T cell function.https://www.frontiersin.org/articles/10.3389/fimmu.2020.629399/fullflucloxacillinHLA-B*57:01drug hypersensitivityhaptenimmunogenicitytransgenic mice |